| First Author | Pi M | Year | 2020 |
| Journal | Sci Rep | Volume | 10 |
| Issue | 1 | Pages | 11143 |
| PubMed ID | 32636482 | Mgi Jnum | J:294038 |
| Mgi Id | MGI:6453033 | Doi | 10.1038/s41598-020-68113-z |
| Citation | Pi M, et al. (2020) Humanized GPRC6A(KGKY) is a gain-of-function polymorphism in mice. Sci Rep 10(1):11143 |
| abstractText | GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targeted genomic humanization of mice by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) system to replace the RKLP sequence in the ICL3 of the GPRC6A mouse gene with the uniquely human KGKY sequence to create Gprc6a-(KGKY-knockin) mice. Knock-in of a human KGKY sequence resulted in a reduction in basal blood glucose levels and increased circulating serum insulin and FGF-21 concentrations. Gprc6a-(KGKY-knockin) mice demonstrated improved glucose tolerance, despite impaired insulin sensitivity and enhanced pyruvate-mediated gluconeogenesis. Liver transcriptome analysis of Gprc6a-(KGKY-knockin) mice identified alterations in glucose, glycogen and fat metabolism pathways. Thus, the uniquely human GPRC6A-(KGKY) variant appears to be a gain-of-function polymorphism that positively regulates energy metabolism in mice. |
